Epidemiological studies on the association of estrogen treatment and cancer in postmenopausal women indicate a clear need for basic investigations of the carcinogenic potential of different types of estrogenic hormones. It is our working hypothesis that a cancer risk is associated with the metabolically activated intermediates of some types of estrogens, and that the mutagenic potential of these estrogens will correlate with their rate of metabolic activation. This hypothesis will be tested using two established mammalian cell culture systems in order to determine the mutagenic and carcinogenic potential of several important types of natural and synthetic estrogens. Their relative effects on single-strand breakage of DNA and mutagenesis at the thymidine kinase locus will be measured in the L5178Y mouse lymphoma cell line. The effects of the metabolic activation products of these estrogens will also be examined in BALB/c3T3 mouse fibroblast cells to determine induction of DNA repair replication, and chemical transformation in this carcinogen-transformable cell line. If our hypothesis is supported by results from one or more of these cellular assays, it will provide a major insight into the mechanism of mutagenesis or carcinogenesis associated with estrogens.